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Xenotransplantation: The Contribution of CRISPR/Cas9 Gene Editing Technology

  • Expanding role of technology in organ transplant (D Axelrod and J Scalea, Section Editors)
  • Published:
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Abstract

Purpose of Review

This review will highlight how gene editing technology using clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) has revolutionized the xenotransplantation field, leading to the first pig-to-human kidney and heart xenotransplants.

Recent Findings

CRISPR/Cas9 gene editing technology has significantly accelerated the development of multi-gene modified pigs to address the major immunological and physiological incompatibilities between pigs and humans. These gene edits include the knockout (KO) of the three porcine-specific glycan epitopes responsible for hyperacute rejection and human transgene expression targeting the coagulation and complement pathways. CRISPR/Cas9 genetic editing has also addressed a critical concern for the potential for cross-species transmission of porcine endogenous retroviruses (PERVs) by allowing the successful generation of pigs with genomically inactivated PERVs to eliminate the risk of viral transmission.

Summary

CRISPR/Cas9 multi-gene edited pigs are likely to be used in the first human clinical xenotransplant trials. While genetic modifications will help protect pig xenografts from innate immune responses, genetic engineering alone will not be sufficient to prevent chronic rejection, given the overwhelming number of possible xenoantigens that can trigger adaptive immune responses and antibody-mediated rejection. Additional immunomodulatory strategies, such as targeted immunosuppression or tolerance induction, will be required for long-term survival of porcine xenografts.

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Abbreviations

10-GE:

10 Gene edited pig

β4GalNT2 :

Gene encoding β-1,4-N-acetyl-galactosaminyltransferase 2

Cas:

CRISPR-associated protein

CMAH :

Gene encoding cytidine monophosphate-N-acetylneuraminic acid hydroxylase

CRISPR:

Clustered regularly interspaced short palindromic repeats

DAF:

Decay-accelerating factor

DSB:

Double-stranded DNA break

ECMO:

Extracorporeal membrane oxygenation

EPCR:

Endothelial cell protein C receptor

GAL:

Galactose-α-1,3-galactose glycan

GGTA1 :

Gene encoding α-1,3-galactosyltransferase

GHR:

Growth hormone receptor

HDR:

Homology-directed repair

HO1:

Hemoxygenase-1

KO:

Knockout

Neu5Gc:

N-glycolylneuraminic acid glycan

NHEJ:

Nonhomologous end-joining

NHP:

Non-human primate

NYU:

New York University

PAM:

Protospacer adjacent motif

PERV:

Porcine endogenous retrovirus

POD:

Post-operative day

RVD:

Repeat-variable di-residue

SDa:

Xenoantigen produced by β-1,4-N-acetyl-galactosaminyltransferase 2

sgRNA:

Single guide RNA

TALEN:

Transcription activator-like effector nuclease

TBM:

Thrombomodulin

UAB:

University of Alabama

UMMC:

University of Maryland Medical Center

ZFN:

Zinc finger nuclease

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  1. Department of Surgery, NYU Langone Transplant Institute, NYU Grossman School of Medicine, 403 East 34th Street—3rd Floor, New York, NY, 10016, USA

    Zoe A. Stewart

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Stewart, Z.A. Xenotransplantation: The Contribution of CRISPR/Cas9 Gene Editing Technology. Curr Transpl Rep 9, 268–275 (2022). https://doi.org/10.1007/s40472-022-00380-3

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